title: Influence of reverse signaling via membrane TNF-alpha on cytotoxicity of NK92 cells.
abstract: Membrane tumor necrosis factor-alpha (mTNF-alpha) serves as a receptor transducing signals into mTNF-alpha-bearing cells. Among human peripheral blood mononuclear cells, natural killer (NK) cells have been reported to be the only cell type constitutively expressing mTNF-alpha, which is involved in the cytotoxicity of resting NK cells. Using an IL-2-dependent human NK cell line, NK92, which constitutively expresses mTNF-alpha, we examined the effect of reverse signaling via mTNF-alpha on cellular activities. When the cells were prestimulated with soluble TNFR1 (sTNFR1) which activated mTNF-alpha-mediated reverse signaling, the cytotoxicity of NK92 cells was significantly increased. Further investigation demonstrated that prestimulation with sTNFR1 augmented exocytosis and mRNA transcription of two cytotoxic molecules, perforin and granzyme B, which could serve as underlying molecular mechanisms by which mTNF-alpha-mediated reverse signaling promoted cytotoxicity of NK cells toward K562 cells. On the other hand, pretreatment of NK92 with sTNFR1 boosted the expression of FasL and TNF-alpha, including both the secretory and membrane forms. These molecules also contribute to the NK-mediated cytotoxicity, although K562 cells are Fas-negative and sTNF-alpha-resistant. Interestingly, the mTNF-alpha reverse signaling was found to act synergistically with IL-2 on NK-mediated cytotoxicity. This synergy markedly promoted the production of secretory as well as membrane cytotoxic molecules which may be responsible for the enhanced NK92-mediated cytotoxicity. Our observations suggest that, via reverse signaling, constitutively expressed mTNF-alpha may sensitize NK cells to activating stimuli, such as IL-2, resulting in increased NK-mediated cytotoxicity through promoting the production of multiple cytotoxic effector molecules.
authors.affiliation: Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China.
authors.forename: Mingxia
authors.initials: M
authors.lastname: Yu
authors.forename: Wenfang
authors.initials: W
authors.lastname: Shi
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Lin
authors.initials: L
authors.lastname: Niu
authors.forename: Qizheng
authors.initials: Q
authors.lastname: Chen
authors.forename: Dan
authors.initials: D
authors.lastname: Yan
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.forename: Wang
authors.initials: W
authors.lastname: Jing
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Jiang
authors.forename: Feng
authors.initials: F
authors.lastname: Wei
authors.forename: Bingjiao
authors.initials: B
authors.lastname: Yin
authors.forename: Wenjie
authors.initials: W
authors.lastname: Zhang
authors.forename: Qingfen
authors.initials: Q
authors.lastname: Li
authors.forename: Zhuoya
authors.initials: Z
authors.lastname: Li
mesh_terms: D016923:Cell Death; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D005089:Exocytosis; D053222:Fas Ligand Protein / Q000378:metabolism; D053804:Granzymes / Q000235:genetics; D006801:Humans; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000166:cytology* / Q000378:metabolism*; D054353:Perforin / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D022142:Secretory Vesicles / Q000378:metabolism; D015398:Signal Transduction; D012995:Solubility; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D053222:Fas Ligand Protein; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D054353:Perforin; D053804:Granzymes